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RO4929097 and Erlotinib Hydrochloride in Treating Patients With Stage IV or Recurrent Non-small Cell Lung Cancer

This study is ongoing, but not recruiting participants.
Information provided by (Responsible Party):
National Cancer Institute (NCI) Identifier:
First received: September 1, 2010
Last updated: February 18, 2015
Last verified: September 2014

This phase I trial studies the side effects and best dose of gamma-secretase/Notch signalling pathway inhibitor RO4929097 (RO4929097) and erlotinib hydrochloride when given together in treating patients with non-small cell lung cancer that is stage IV or has come back. RO4929097 and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition Intervention Phase
Recurrent Non-Small Cell Lung Carcinoma
Stage IV Non-Small Cell Lung Cancer
Drug: Erlotinib Hydrochloride
Drug: Gamma-Secretase Inhibitor RO4929097
Other: Pharmacological Study
Other: Laboratory Biomarker Analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Addition of the Gamma-Secretase Inhibitor RO4929097 to Erlotinib in Patients With Advanced Non-small Cell Lung Cancer (NSCLC)

Resource links provided by NLM:

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum-tolerated dose of RO4929097 and erlotinib hydrochloride defined as the highest dose tested causing dose limiting toxicity in < 2/6 patients assessed using National Cancer Institute (NCI) CTCAE version 4.0 (Dose escalation phase) [ Time Frame: At least 3 weeks after day 1 of course 1 ] [ Designated as safety issue: Yes ]
  • Incidence of adverse events assessed using NCI CTCAE version 4.0 (Dose escalation phase) [ Time Frame: Within 30 days of last drug dose ] [ Designated as safety issue: Yes ]
  • Response rate by RECIST 1.1 (Expansion cohort) [ Time Frame: Up to 12 weeks ] [ Designated as safety issue: No ]
  • Percentage of tumor shrinkage (Expansion cohort) [ Time Frame: Up to 6 weeks ] [ Designated as safety issue: No ]
    Will be correlated with response and baseline expression of biomarkers. The differences before and after treatment will be assessed using a paired-t test on the log-transformed tumor sizes and a Wilcoxon signed-rank test.

  • Percentage of change in expression of Notch and other tumor and blood biomarkers (Expansion cohort) [ Time Frame: Baseline to 6 weeks ] [ Designated as safety issue: No ]
    The differences before and after treatment will be assessed using a paired-t test on the log-transformed tumor sizes and a Wilcoxon signed-rank test.

  • Time to progression (Expansion cohort) [ Time Frame: Up to 12 weeks ] [ Designated as safety issue: No ]
    Will be correlated with baseline expression or biomarkers.

Other Outcome Measures:
  • Efficacy of this combination in unselected patients and in patients with intrinsic or acquired erlotinib resistance (Dose escalation phase) [ Time Frame: Up to 12 weeks ] [ Designated as safety issue: No ]
  • Pre-therapy tumor expression of Notch and other tumor and blood biomarkers (Dose escalation phase) [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Exploratory assessments of correlations of tumor shrinkage and response on the combination with pre-therapy tumor expression of Notch and other tumor and blood biomarkers will be conducted.

  • Stem cell markers [ Time Frame: Up to 6 weeks ] [ Designated as safety issue: No ]
    Correlations between Notch pathway markers and stem cell markers will be assessed.

  • Host Notch pathway gene polymorphisms [ Time Frame: Up to 6 weeks ] [ Designated as safety issue: No ]
    Correlations between Notch pathway gene polymorphisms and tumor and blood biomarkers will be assessed. Correlations between Notch pathway gene polymorphisms and tumor shrinkage/response on therapy will also be assessed.

Estimated Enrollment: 39
Study Start Date: August 2010
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (erlotinib, RO4929097)
Patients receive erlotinib hydrochloride PO QD on days 1-21 and gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: Erlotinib Hydrochloride
Given PO
Other Name: Cp-358,774
Drug: Gamma-Secretase Inhibitor RO4929097
Given PO
Other Name: RO4929097
Other: Pharmacological Study
Correlative studies
Other Name: pharmacological studies
Other: Laboratory Biomarker Analysis
Correlative studies

  Show Detailed Description


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Dose-escalation portion:

    • Patients must have histologically or cytologically confirmed diagnosis of incurable NSCLC
    • Preference will be given to patients with NSCLC who have been treated with erlotinib, and have either responded initially and then experienced subsequent growth in one or more tumor deposits while continuing erlotinib (acquired resistance) or patients who have been treated with erlotinib and failed to demonstrate any response to it (intrinsic resistance)
  • Expansion cohort: patients must satisfy each of the following criteria:

    • Histologically or cytologically confirmed non-small cell lung cancer that is incurable (stage IV or recurrent)
    • Patients must not have received prior anti-EGFR therapy
  • Patients on both the dose escalation portion of the study and in the Expansion Cohort portion must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 10 mm with computed tomography (CT) scan with cuts at 2.5 or 5 mm
  • Patients on both portions of the study must have tumor amenable to core biopsy (or to incisional, excisional, or punch biopsy) for research purposes; the collaborating interventional radiologists will make the determination whether or not the patient has a tumor amenable to biopsy and whether or not the patient is medically an appropriate candidate for tumor biopsy
  • Any prior anticancer systemic therapy or radiotherapy must have been completed at least 4 weeks prior to initiation of therapy on this study; (Exception: patients may be entered within 2 weeks of radiotherapy if the radiotherapy was restricted to femur below the trochanter, humerus or more distal limb areas)
  • Dose escalation portion:

    • Unlimited prior therapy is permitted (including prior anti-EGFR therapy), with the exception that patients who have received prior therapy with a gamma-secretase inhibitor are not eligible
    • Prior therapy is not required
    • Preference will be given to NSCLC patients who have been treated with erlotinib with evidence of acquired or intrinsic resistance to erlotinib
  • Expansion cohort:

    • Patients may have received an unlimited number of prior systemic regimens for NSCLC (as adjuvant therapy, as therapy for locally advanced disease or as therapy for advanced disease) provided they have not received prior anti-EGFR therapy (small molecule or antibody, etc) or prior gamma-secretase inhibitors
    • Prior therapy is not required
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 60%)
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets>= 100,000/mcL
  • Hemoglobin >= 9 g/dL
  • Total bilirubin within normal institutional limits
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 X institutional upper limit of normal
  • Creatinine =< 1.5 X institutional upper limit of normal
  • International normalized ratio (INR) =< 1.7 X upper limit of normal (ULN) and the patient must not have received aspirin or Coumadin and the patient must not have received aspirin or Coumadin within the previous week or a therapeutic dose of a heparin product within the previous 24 hours
  • Women of childbearing potential must use two forms of contraception (i.e., barrier contraception and one other method of contraception) from at least 2 weeks prior to initiation of therapy on this study, for the duration of study participation, and for at least 2 months post-treatment; should a woman become pregnant or suspect she is pregnant while she or her partner are participating in this study and for 2 months after study participation, the patient should inform the treating physician immediately

    • Women of childbearing potential are required to have a negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within 14 days prior to the first dose of RO4929097 and a negative serum or urine pregnancy test within 24 hours prior to the first dose of RO4929097; following initiation of therapy with RO4929097, a pregnancy test (serum or urine) will be administered every 3 weeks while on study; a positive urine test must be confirmed by a serum pregnancy test; prior to dispensing RO4929097, the investigator or designate must confirm and document the patient's use of two contraceptive methods, dates of negative pregnancy test, and confirm the patient's understanding of the teratogenic potential of RO4929097
    • Patients with a positive pregnancy test who are unlikely to be pregnant may be considered for entry on this trial if they are deemed to be unlikely to be pregnant by an obstetrician or gynecologist and if the study sponsor is in agreement with their study entry
    • Female patients of childbearing potential are defined as patients who do not fall into either of the categories listed above and to whom any of the following apply:

      • Patients with regular menses
      • Patients, after menarche with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding
      • Women who have had tubal ligation
    • Female patients may be considered to NOT be of childbearing potential for the following reasons:

      • The patient has undergone total abdominal hysterectomy with bilateral salpingo-oophorectomy or bilateral oophorectomy
      • The patient is medically confirmed to be menopausal (no menstrual period) for 24 consecutive months
  • Men participating in the study must also use 2 methods of contraception including 1 barrier method
  • Breastfeeding should be discontinued if the mother is treated with RO4929097
  • Patients with asymptomatic or minimally symptomatic brain metastases will not be required to undergo cranial radiation prior to being considered for this trial, and are eligible provided that it is not anticipated that they will require any of the following over the course of study treatment:

    • Corticosteroids for control of cerebral edema
    • Enzyme-inducing anticonvulsants
    • Radiotherapy, surgery, or other local therapy for the brain metastases
  • Able to swallow oral medications

Exclusion Criteria:

  • Patients may not have received other systemic therapy or radiotherapy for their cancer within the previous 4 weeks prior to planned first day of therapy on this trial; (Exception: patients may be entered within 2 weeks of radiotherapy if the radiotherapy was restricted to distal limbs such as femur below the trochanter, humerus or more distal limb areas; in addition, patients in the dose escalation portion who have previously received erlotinib may start therapy on this trial as early as 1 week after stopping prior erlotinib provided all other study entry criteria are met)
  • Patients on the expansion cohort may not have received prior anti-EGFR therapy (small molecule tyrosine kinase inhibitor [TKI] or antibody); (Note: this in contrast to the dose escalation portion of the study in which patients with prior anti-EGFR therapy will be eligible)
  • Patients may not be receiving any other investigational agents
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to RO4929097, OSI-774 or other agents used in the study
  • Patients taking medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible
  • Caution should be exercised when dosing RO4929097 concurrently with CYP3A4 substrates, inducers, and/or inhibitors; furthermore, patients who are taking concurrent medications (other than erlotinib) that are strong inducers/inhibitors or substrates of CYP3A4 should be switched to alternative medications; if such patients cannot be switched to alternative medications, they will be ineligible to participate in this study; if a patient is taking a strong CYP3A4 inhibitor/inducer other than the 2 study drugs, they should be switched to an alternative drug
  • Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption
  • Diarrhea > grade 1 despite appropriate therapy
  • Patients who are known to be serologically positive for hepatitis A, B or C are ineligible
  • Patients with > grade 1 (by Common Terminology Criteria for Adverse Events [CTCAE] criteria) hyponatremia or hypocalcemia (based on measurement of ionized calcium) despite appropriate medical management are excluded from this study, as are patients with hypophosphatemia (serum phosphate below the lower limit of normal for the institution), hypomagnesemia, (serum magnesium below the lower limit of normal), hypokalemia, or hyperkalemia (serum potassium outside normal limits) despite appropriate medical management
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring systemic therapy (with antibiotics, antiviral or antifungal agents), symptomatic congestive heart failure, unstable angina pectoris, angina at rest, a history of torsades de pointes, potentially life-threatening cardiac arrhythmias (patients are permitted to have chronic, stable atrial fibrillation, premature atrial or ventricular contractions, sinus tachycardia, provided the rate is controlled at < 115 per minute, and sinus bradycardia, provided the rate is > 50 per minute), myocardial infarction within the previous 3 months, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
  • Cardiovascular: baseline corrected QT interval using Fridericia's formula (QTcF) > 450 msec (male) or QTcF > 470 msec (female)
  • Patients requiring drugs that are known to cause Torsades de pointes and/or prolonged corrected QT (QTc) intervals are excluded; patients requiring drugs with a possible but unproven association with Torsades de pointes and/or QTc prolongation may be eligible, but will require additional electrocardiogram assessments, as outlined
  • Patients who have not recovered to < CTCAE grade 2 toxicities related to prior therapy are not eligible to participate in this study
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01193881

United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Principal Investigator: Don Gibbons M.D. Anderson Cancer Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI) Identifier: NCT01193881     History of Changes
Other Study ID Numbers: NCI-2010-01975, NCI-2010-01975, 2009-0769, 8508, N01CM62202, P30CA016672, U01CA062461, N01CM00039
Study First Received: September 1, 2010
Last Updated: February 18, 2015
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Bronchial Neoplasms
Carcinoma, Bronchogenic
Lung Diseases
Neoplasms by Site
Respiratory Tract Diseases
Respiratory Tract Neoplasms
Thoracic Neoplasms
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protein Kinase Inhibitors processed this record on February 27, 2015